Background and purpose
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity. Experimental approach: Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice. Key
Purpose
11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) regulates tissue-specific glucocorticoid metabolism and its impaired expression and activity are associated with major diseases. Pharmacological inhibition of 11β-HSD1 is considered a promising therapeutic strategy. This study investigated whether alternative 7-oxo bile acid substrates of 11β-HSD1 or the ratios to their 7-hydroxy products can serve as biomarkers for decreased enzymatic activity. Experimental approach: Bile acid profiles were measured by ultra-HPLC tandem-MS in plasma and liver tissue samples of four different mouse models with decreased 11β-HSD1 activity: global (11KO) and liver-specific 11β-HSD1 knockout mice (11LKO), mice lacking hexose-6-phosphate dehydrogenase (H6pdKO) that provides cofactor NADPH for 11β-HSD1 and mice treated with the pharmacological inhibitor carbenoxolone. Additionally, 11β-HSD1 expression and activity were assessed in H6pdKO- and carbenoxolone-treated mice. Key
Results
The enzyme product to substrate ratios were more reliable markers of 11β-HSD1 activity than absolute levels due to large inter-individual variations in bile acid concentrations. The ratio of the 7β-hydroxylated ursodeoxycholyltaurine (UDC-Tau) to 7-oxolithocholyltaurine (7oxoLC-Tau) was diminished in plasma and liver tissue of all four mouse models and decreased in H6pdKO- and carbenoxolone-treated mice with moderately reduced 11β-HSD1 activity. The persistence of 11β-HSD1 oxoreduction activity in the face of H6PD loss indicates the existence of an alternative NADPH source in the endoplasmic reticulum. Conclusions and implications: The plasma UDC-Tau/7oxo-LC-Tau ratio detects decreased 11β-HSD1 oxoreduction activity in different mouse models. This ratio may be a useful biomarker of decreased 11β-HSD1 activity in pathophysiological situations or upon pharmacological inhibition. Linked articles: This article is part of a themed issue on Oxysterols, Lifelong Health and Therapeutics. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.16/issuetoc.